Xelevia tablets 100mg, No. 28

• Monotherapy: as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes;

• Combination therapy: type 2 diabetes mellitus to improve glycemic control in combination with metformin or PPAR-agonists? (for example, thiazolidinedione) when diet and exercise in combination with monotherapy with the listed agents do not lead to adequate glycemic control.

Inside. Single dose - 100 mg 1 time / day. In case of renal failure, correction of the dosage regimen is required.

Beige film-coated tablets, round, biconvex, engraved with '277' on one side and smooth on the other.

1 tab. sitagliptin phosphate monohydrate 128.5 mg,

which corresponds to the content of sitagliptin 100 mg

Excipients: microcrystalline cellulose - 123.8 mg, calcium hydrogen phosphate unmilled - 123.8 mg, croscarmellose sodium - 8 mg, magnesium stearate - 4 mg, sodium stearyl fumarate - 12 mg.

• Type 1 diabetes mellitus;

• diabetic ketoacidosis;

• pregnancy;

• lactation period (breastfeeding);

• children and adolescents under the age of 18;

• hypersensitivity to sitagliptin.

pharmachologic effect

Oral hypoglycemic agent, highly selective inhibitor of dipeptidyl peptidase 4 (DPP-4).

Sitagliptin differs in chemical structure and pharmacological action from analogs of glucagon-like peptide-1 (GLP-1), insulin, sulfonylurea derivatives, biguanides, ?-receptor agonists activated by the peroxisome proliferator (PPAR-?), alpha-glycosidase inhibitors, amylin analogs. By inhibiting DPP-4, sitagliptin increases the concentration of 2 known hormones of the incretin family: GLP-1 and glucose-dependent insulinotropic peptide (GIP). Hormones of the incretin family are secreted in the intestines during the day, and their level rises in response to food intake. Incretins are part of the internal physiological system for the regulation of glucose homeostasis. At normal or elevated blood glucose levels, hormones of the incretin family increase insulin synthesis,as well as its secretion by pancreatic ?-cells due to signaling intracellular mechanisms associated with cyclic AMP.

GLP-1 also contributes to the suppression of increased secretion of glucagon by the ?-cells of the pancreas. A decrease in glucagon concentration against the background of an increase in insulin levels contributes to a decrease in the production of glucose by the liver, which ultimately leads to a decrease in glycemia.

At a low blood glucose concentration, the listed effects of incretins on insulin release and a decrease in glucagon secretion are not observed. GLP-1 and GIP do not affect glucagon release in response to hypoglycemia. Under physiological conditions, the activity of incretins is limited by the DPP-4 enzyme, which rapidly hydrolyzes incretins to form inactive products.

Sitagliptin prevents the hydrolysis of incretins by the DPP-4 enzyme, thereby increasing the plasma concentrations of the active forms of GLP-1 and GIP. By increasing the level of incretins, sitagliptin increases the glucose-dependent release of insulin and helps to reduce the secretion of glucagon. In patients with type 2 diabetes mellitus with hyperglycemia, these changes in insulin and glucagon secretion lead to a decrease in the level of glycated hemoglobin HbA1C and a decrease in plasma glucose concentration, determined on an empty stomach and after exercise testing.

In patients with type 2 diabetes mellitus, taking one dose of sitagliptin leads to inhibition of the activity of the DPP-4 enzyme for 24 hours, which leads to an increase in the level of circulating incretins GLP-1 and GIP by 2-3 times, an increase in the plasma concentration of insulin and C-peptide , a decrease in the concentration of glucagon in the blood plasma, a decrease in fasting glycemia, as well as a decrease in glycemia after glucose load or food load.

Pharmacokinetics

The pharmacokinetics of sitagliptin has been studied in healthy individuals and patients with type 2 diabetes mellitus.

After oral administration of the drug at a dose of 100 mg in healthy individuals, there is a rapid absorption of sitagliptin with the achievement of Cmax after 1-4 hours. AUC increases in proportion to the dose and is 8.52 ?mol in healthy subjects? h when taken orally at a dose of 100 mg, Cmax was 950 nmol. The absolute bioavailability of sitagliptin is approximately 87%. Intra- and interindividual coefficients of variability of sitagliptin AUC are insignificant. The simultaneous intake of fatty foods does not affect the pharmacokinetics of sitagliptin.

Plasma AUC of sitagliptin increased by approximately 14% after the next dose of 100 mg, after reaching equilibrium after taking the first dose. After a single dose of 100 mg of the drug, the average Vd of sitagliptin in healthy volunteers was approximately 198 liters. Plasma protein binding of sitagliptin is 38%.

Only a small part of the drug that has entered the body is metabolized. After oral administration of 14C-labeled sitagliptin, approximately 16% of the radioactive drug was excreted as its metabolites. Traces of 6 sitagliptin metabolites were found, probably lacking DPP-4 inhibitory activity. In vitro studies have shown that the primary enzyme involved in the limited metabolism of sitagliptin is CYP3A4 with the participation of CYP2C8.

Approximately 79% of sitagliptin is excreted unchanged in the urine. Within 1 week after taking the drug by healthy volunteers, 14C-labeled sitagliptin was excreted: with urine - 87% and feces - 13%. T1 / 2 of sitagliptin when taken orally at a dose of 100 mg is approximately 12.4 hours. Renal clearance is approximately 350 ml / min.

Excretion of sitagliptin is carried out primarily by excretion by the kidneys by the mechanism of active tubular secretion. Sitagliptin is a substrate for the third type of human organic anion transporter (hOAT-3), which may be involved in the process of excretion of sitagliptin by the kidneys. Sitagliptin is also a substrate for p-glycoprotein, which may also be involved in the renal elimination of sitagliptin.

Side effect

Respiratory system: upper respiratory tract infections (100 mg - 6.8%, 200 mg - 6.1%, placebo - 6.7%), nasopharyngitis (100 mg - 4.5%, 200 mg - 4.4%, placebo - 3.3%).

From the side of the central nervous system: headache (100 mg - 3.6%, 200 mg - 3.9%, placebo - 3.6%).

From the digestive system: diarrhea (100 mg - 3%, 200 mg - 2.6%, placebo - 2.3%), abdominal pain (100 mg - 2.3%, 200 mg - 1.3%, placebo - 2.1%), nausea (100 mg - 1.4%, 200 mg - 2.9%, placebo - 0.6%), vomiting (100 mg - 0.8%, 200 mg - 0.7%, placebo - 0.9%), diarrhea (100 mg - 3%, 200 mg - 2.6% , placebo - 2.3%).

From the musculoskeletal system: arthralgia (100 mg - 2.1%, 200 mg - 3.3%, placebo - 1.8%).

From the endocrine system: hypoglycemia (100 mg - 1.2%, 200 mg - 0.9%, placebo - 0.9%).

On the part of laboratory parameters: at doses of 100 mg / day and 200 mg / day - an increase in uric acid by approximately 0.2 mg / dL compared with placebo (average level 5-5.5 mg / dL) in patients who received the drug at a dose of 100 mg / day and 200 mg / day. No cases of gout have been reported.

Application during pregnancy and lactation

Use during pregnancy and lactation (breastfeeding) is contraindicated.

Application in children

The drug is contraindicated for use in children and adolescents under the age of 18 years.

Use in elderly patients

Elderly patients are more likely to develop renal failure. Accordingly, as in other age groups, dose adjustment is necessary in patients with severe renal failure.

special instructions

Use with caution in patients with renal insufficiency. In case of moderate and severe renal failure, as well as in patients with end-stage renal failure who require hemodialysis, a dosage adjustment is required.

Elderly patients are more likely to develop renal failure. Accordingly, as in other age groups, dose adjustment is necessary in patients with severe renal failure.

Drug interactions

There was a slight increase in AUC (11%), as well as average Cmax (18%) of digoxin when used together with sitagliptin. This increase is not considered clinically significant.

There was an increase in AUC and Cmax of sitagliptin by 29% and 68%, respectively, in patients with the combined use of sitagliptin in a single dose of 100 mg and cyclosporin (a potent inhibitor of P-glycoprotein) in a single dose of 600 mg. These changes in the pharmacokinetic parameters of sitagliptin are not considered clinically significant.